Malignant B-cell intra-clonal diversification: Following the yarn in the labyrinth

The generation of cellular diversity is considered a key factor in the development of cancer. The research of B-cell malignancies provides a unique opportunity to study the origin, regulation, and physiological significance of diversification mechanisms, due to active alterations of the immunoglobulin genes in these cells. These genes provide a distinctive marker common to all of the malignant cells in a single patient, and, in addition, serve as 'molecular clocks' that are associated with specific developmental stages of the B-cell lineage. Moreover, the mechanisms underlining the normal molecular alterations of the immunoglobulin genes may also generate genetic lesions associated with the progression of B-cell malignancies. Analyses of cellular populations of several types of B-cell malignancies revealed remarkable diversity with respect to different properties of the cells, including stages of differentiation, accumulation of mutations, gene expression, and drug resistance. These studies indicate that the diversity of malignant B-cells is generated along two major dimensions. One is aligned with the developmental program of B-cells, where malignant cells of a single clone, but at several distinct differentiation stages, can be found in a single patient. The second dimension of diversity is established by the location of the malignant cells in a specific tissue, or in specialized microenvironmental niches within the tissue. Elements composing the microenvironment, including stromal cells, the extracellular matrix, and soluble factors, regulate the gene expression profile in the malignant cells, and hence affect also their physiology. The involvement of microenvironmental factors in the development of B-cell malignancies may provide novel targeting opportunities for therapy.